A simple way to estimate the median time and compare survival distributions in analgesic trials under informative censoring.

We discuss the problem of estimating the median time and comparison of survival curves when data are nonrandomly censored in analgesic trials. In these trials patients experience post-surgical pain at the time of randomization. Time to onset of analgesia is measured by patient-administered stopwatches. An effective analgesic is one for which the median time to onset is "short." The study design allows patients to remedicate if their pain persists, and this remedication prior to pain relief censors the time-to-onset measures. The time to onset for patients who remedicate is nonrandomly censored. Assuming noninformative censoring yields misleading results with the Kaplan-Meier method (for estimation of median time) and the log-rank test (for comparison of survival curves). This assumption can also obscure the superior effect of an effective analgesic over an ineffective one. We propose a simple and intuitive way to handle the nonrandomly censored data in analgesic trials in order to (a) estimate the median time to pain relief and (b) compare the survival distributions between treatments. The method proposed is applied to data collected from an acute pain clinical trial, and the results are discussed.

Selecting screening criteria for clinical trials: an example from the Systolic Hypertension in the Elderly Program.

In clinical trials that study people with a continuous measure defined categorically, even repeated measurements within a visit and over successive visits do not prevent error-free classification. We describe the design of a screening procedure for the Systolic Hypertension in the Elderly Program (SHEP), a randomized clinical trial designed to test whether regular administration of antihypertensive medication reduces the risk of stroke in elderly persons with isolated systolic hypertension. Data from a pilot study performed before the inauguration of SHEP allowed empirical study of a variety of possible screening rules for SHEP. A desirable screening rule would require only two screening visits, would lead to a randomized cohort with high mean systolic blood pressure, and would not impede recruitment. We emphasize two classes of rules, "serial" and "conditional." A serial rule uses only the values observed at a given screen to determine eligibility to proceed to the next screen. A conditional rule uses the value observed at a given screen along with values already observed to determine eligibility to proceed. For the SHEP study, we chose a conditional rule for screening because of its efficiency in identifying eligible participants. Our approach to selection of screening rules should be applicable to other clinical trials in which the measurement that defines the primary entry criterion has considerable measurement error.

Optimal surgery for papillary thyroid carcinoma.

There has been a long, unresolved debate regarding the operation of choice for well differentiated carcinoma of the thyroid. We therefore analyzed the feasibility, scope, sample size, and length of follow-up required to determine the optimal operation for papillary thyroid carcinoma. A statistical approach was used to design a randomized prospective trial comparing the endpoints of complications, recurrence, and cause-specific mortality. A complication comparison trial is prohibitive owing to the large population required--approximately 12,000 randomized patients. A recurrence trial appears feasible based on sample size: approximately 360 to 800 patients with a 6 to 10-year follow-up. However, recurrence detection would be severely compromised in the lobectomy arm, and a unilateral lag-time bias would occur. A cause-specific mortality trial proves to be the least objectionable, although a large sample size (n = 3100) would be required. Such a trial is critically dependent on the ability to select an appropriate endpoint. A cause-specific mortality trial proves to be the most objective and statistically valid endpoint.

Statistical design of the Child and Adolescent Trial for Cardiovascular Health (CATCH): implications of cluster randomization.

This paper describes some statistical considerations for the Child and Adolescent Trial for Cardiovascular Health (CATCH), a large-scale community health trial sponsored by the National Heart, Lung, and Blood Institute. The trial involves randomization of entire schools rather than individual students to the experimental arms. The paper discussed the implications of this form of randomization for the design and analysis of the trial. The power calculations and analysis plan for the trial are presented in detail. The handling of outmigrating and immigrating students is also discussed.

Lack of blood pressure effect with calcium and magnesium supplementation in adults with high-normal blood pressure. Results from Phase I of the Trials of Hypertension Prevention (TOHP). Trials of Hypertension Prevention (TOHP) Collaborative Research Group.

Phase I of the Trials of Hypertension Prevention (TOHP) was a randomized, multicenter investigation that included double-blind, placebo-controlled testing of calcium and magnesium supplementation among 698 healthy adults (10.5% blacks and 31% women) aged 30 to 54 years with high-normal diastolic blood pressure (DBP) (80 to 89 mm Hg). Very high compliance (94 to 96% by pill counts) with daily doses of 1 g of calcium (carbonate), 360 mg of magnesium (diglycine), or placebos was corroborated for the active supplements by significant net increases in all urine and serum compliance measures in white men and for urine compliance measures in white women. Overall, neither calcium nor magnesium produced significant changes in blood pressure at 3 and 6 months. Analyses stratified by baseline intakes of calcium, magnesium, sodium, or initial blood pressures also showed no effect of supplementation. These analyses suggested that calcium supplementation may have resulted in a DBP decrease in white women and that response modifiers in this subgroup might have included lower initial urinary calcium levels, urinary sodium levels, or lower body mass index. However, overall analyses indicated that calcium and magnesium supplements are unlikely to lower blood pressure in adults with high-normal DBP. The subgroup analyses, useful to formulate hypotheses, raise the possibility of a benefit to white women, which requires testing in future trials.

Reducing the fat content of ground beef in a school foodservice setting.

OBJECTIVE: The objective was to develop and test the nutrient results of a two-step defatting procedure with ground beef in a school foodservice setting as part of the Eat Smart school lunch component of the Child and Adolescent Trial for Cardiovascular Health (CATCH). SETTING AND DESIGN: The procedure was tested in a school foodservice setting to determine the effect of cooking, draining, and subsequent rinsing with hot water on nutrient composition of ground beef. Samples of raw; cooked and drained; and cooked, drained, and rinsed ground beef were collected and chemically analyzed for total fat, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, cholesterol, iron, and niacin content. RESULTS: The results indicated that the total fat and the saturated, monounsaturated, and polyunsaturated fatty acids were significantly reduced 31% to 35% from cooking and draining (P < .005) and reduced by an additional 25% to 30% from rinsing (P < .0001). Cholesterol content was not affected. Iron content increased after the cooking and rinsing, although not significantly. Niacin content significantly decreased during rinsing by 28% (P < .005), but the mean value of the cooked, drained, and rinsed ground beef still met the criteria of the Food and Drug Administration for a good source of niacin. APPLICATION: The two-step defatting procedure developed for use in a school foodservice setting lowers the total fat and saturated fatty acid content of ground beef without substantially reducing its nutritional quality.

Energy intake and physical activity in relation to indexes of body fat: the National Heart, Lung, and Blood Institute Growth and Health Study.

The relationship between energy intake, physical activity, and body fat was investigated in the baseline visit of 2379 black and white girls aged 9-10 y enrolled in the National Heart, Lung, and Blood Institute Growth and Health Study. Three-day food records, three-day physical activity diaries, physical-activity-patterns questionnaires, and an assessment of the number of hours of television and video watched were obtained. Multivariate-regression analyses showed that age, the number of hours of television and video watched, the percent of energy from saturated fatty acids, and the activity-patterns score best explained the variation in body mass index and sum of three skin-fold-thickness measurements for black girls. The best model for white girls included age, the number of hours of television and video watched, and the percent of energy from total fat. These results indicate that body fatness is related to energy intake and expenditure in both black and white girls. Longitudinal studies will help assess the value of these variables in predicting changes in body fat.

Indexes of obesity and comparisons with previous national survey data in 9- and 10-year-old black and white girls: the National Heart, Lung, and Blood Institute Growth and Health Study.

OBJECTIVE: To (1) describe anthropometric and body-size measurements in the National Heart, Lung, and Blood Institute Growth and Health Study (NGHS) population at baseline and (2) examine potential secular trends in the prevalence of obesity in young black and white girls by comparing NGHS baseline data with those of the two National Health and Nutrition Examination Surveys (NHANES I and II) (measured before the NGHS). DESIGN: Cross-sectional analysis of cohort baseline data. SETTING: Recruitment in selected schools (Cincinnati and Berkeley) and among the membership of a group health association (Westat). PATIENTS: Enrolled 2379 girls, 9 and 10 years of age, including 1213 black and 1166 white. MEASUREMENTS: Anthropometric measures, including height, weight, and triceps and subscapular skin folds. Body mass index was used as a measure of body size. Nine- and ten-year-old black girls were taller, heavier, and had larger skin folds than white girls. Compared with age-similar girls in the 1970s, girls in the present study are taller and heavier and have thicker skin folds. The differences in body size were most notable among black girls. CONCLUSIONS: Black girls have a greater body mass than white girls even as young as 9 and 10 years of age. The prevalence of obesity appears to be increasing among young girls, especially in black girls. This progression, if not altered, could lead to increased disease in the future for adult women, particularly black women.

Statistical considerations in monitoring the Systolic Hypertension in the Elderly Program (SHEP).

The Systolic Hypertension in the Elderly Program (SHEP), a randomized, double-masked, placebo-controlled trial of 4736 persons, was designed to assess the efficacy of antihypertensive drug treatment to reduce the risk of fatal and nonfatal strokes among people age 60 and over with isolated systolic hypertension. The statistical method used in interim monitoring of results was conditional power (or stochastic curtailment). The findings did not become conclusive until near the completion of the trial, and therefore SHEP was continued to its scheduled closing date. The trial demonstrated a 36% reduction in the incidence of stroke in the active treatment group (P = .0003). In addition to evaluating overall efficacy of treatment, the monitoring process considered such other issues as nonstroke outcomes, lag time between first report of stroke and final confirmation of stroke diagnosis, consistency of results across subgroups, and completeness of follow-up. The purpose of this article is to review these factors with primary emphasis on the statistical aspects.

Angiogenic effects of low molecular weight heparin in patients with stable coronary artery disease: a pilot study.

OBJECTIVES: The study was designed to assess the feasibility of conducting a trial to investigate whether exercise and low molecular weight heparin therapy with dalteparin sodium (Fragmin) would improve collateral function to the ischemic myocardium in patients with coronary artery disease. BACKGROUND: The severity of myocardial ischemia in patients with coronary artery disease is at least partly dependent on the status of the collateral circulation. Therefore, improvement in collateral function would potentially provide a unique way of alleviating myocardial ischemia. Because the combination of ischemia and heparin has previously been demonstrated to enhance collateral growth, we studied the anti-ischemic effects of combined treatment with dalteparin sodium and exercise-induced ischemia in patients with coronary artery disease. METHODS: Twenty-three patients with stable coronary artery disease were randomized to receive either subcutaneous dalteparin sodium or placebo for a 4-week period. Patients received either placebo or 10,000 IU of dalteparin sodium by subcutaneous injection once daily for weeks 1 and 2 and 5,000 IU daily for weeks 3 and 4. During the 1st 2 weeks, patients were exercised to ischemia three times a day. At baseline and 4 weeks after treatment, treadmill exercise testing, exercise radionuclide ventriculography and 48-h ambulatory ST segment monitoring were performed. RESULTS: Eight (80%) of the 10 dalteparin sodium-treated patients compared with 4 (31%) of 13 placebo-treated patients (p < 0.02) had an increased rate-pressure product at the onset of 1 mm of ST segment depression. The duration of exercise to ischemia increased in all patients treated with low molecular weight heparin and in 62% of placebo-treated patients (p < 0.03). The number and duration of episodes of ST segment depression during ambulatory monitoring decreased by 30% and 35%, respectively (p < 0.05), in the dalteparin sodium group but were unchanged in the placebo group. The decrease in left ventricular ejection fraction with exercise was lower in 80% of dalteparin sodium-treated patients compared with 54% of placebo-treated patients (p = 0.06). When all five factors reflecting collateral function were considered together in a multivariate analysis of variance, there was a significant improvement in low molecular weight heparin-treated patients compared with placebo-treated patients (p = 0.014). CONCLUSIONS: This study provides preliminary evidence suggesting that exercise and low molecular weight heparin therapy with dalteparin sodium lessen myocardial ischemia and that the improvement is likely to be mediated by enhanced collateral function.

Circadian variation in ischemic threshold. A mechanism underlying the circadian variation in ischemic events.

BACKGROUND: There is a circadian pattern in the occurrence of cardiac events in patients with coronary artery disease. Whether changes in coronary vascular tone contribute to these phenomena is unknown. We measured the ischemic threshold, defined as either the heart rate or rate-pressure product at 1-mm ST segment depression during treadmill exercise and used it as an index of the lowest coronary vascular resistance; the premise was that when ischemic threshold became lower, coronary vascular resistance was higher, and vice versa. METHODS AND RESULTS: Fifteen patients (group A) with stable coronary artery disease underwent four identical treadmill exercise tests in 24 hours, and ischemic threshold was measured as the heart rate at the onset of 1-mm ST depression. Before each treadmill test, postischemic forearm vascular resistance was measured after 5 minutes of forearm occlusion, using strain-gauge plethysmography. Sixteen additional patients (group B) underwent two treadmill tests at 8 AM and 1 PM, and ischemic threshold was measured as the heart rate-blood pressure product at 1-mm ST depression. A circadian variation was noted: In group A, the heart rate-derived ischemic threshold was lower at 8 AM and 9 PM compared with noon and 5 PM (p less than 0.03). Also, in group B, the rate-pressure product-derived ischemic threshold was 8 +/- 2% lower at 8 AM compared with 1 PM (p = 0.008). A circadian variation parallel to the observed variation in ischemic threshold was also noted in the postischemic forearm blood flow, which was lower in the morning and at night (p less than 0.004). There was a strong correlation between postischemic forearm blood flow and ischemic threshold (p less than 0.0001), such that ischemic threshold was lower at the time of day when postischemic forearm blood flow was lower, and vice versa. CONCLUSIONS: A lower ischemic threshold in the morning suggests that the ischemia-induced coronary vascular resistance is increased at this time, a finding supported by a similar variation in postischemic forearm vascular resistance. Parallel changes in forearm and coronary resistance suggest that generalized (neural or humoral factors) rather than local factors are responsible for the observed circadian changes. Increased coronary tone in the mornings may not only contribute to the higher incidence of transient ischemia but may help trigger acute cardiac events at this time.

Degree of left ventricular hypertrophy in patients with hypertrophic cardiomyopathy and chronic atrial fibrillation.

It has been generally assumed that most patients with hypertrophic cardiomyopathy (HC) who develop atrial fibrillation (AF) have marked left ventricular (LV) hypertrophy and subaortic obstruction. The morphologic and functional features of this subset of patients with HC have not been systematically investigated. The LV morphology and functional profile of 46 patients with HC and chronic AF were compared with those of 81 control patients with HC and normal sinus rhythm. Contrary to expectations, LV hypertrophy (assessed with 2-dimensional echocardiography) was substantially less marked in the patients with AF than in the control patients, and prevalence of subaortic obstruction was similar in the 2 groups. Maximal LV wall thickness and wall thickness index were lower in patients with AF (18 +/- 2 and 56 +/- 7 mm, respectively) than in control patients (22 +/- 6 and 67 +/- 16 mm, respectively; p less than 0.001). Furthermore, mild LV hypertrophy (maximal LV wall thickness less than or equal to 17 mm confined to 1 ventricular segment) was almost twice as frequent in patients with AF (63%) than in control patients (36%; p less than 0.005). Subaortic obstruction was present in 9 patients with AF (20%) and in 28 control patients (35%; p greater than 0.05). In a subgroup of 22 patients with AF who were followed for 4 to 10 years, 5 patients had marked LV wall thinning (greater than or equal to 5 mm, range 5 to 14). In conclusion, these results demonstrate that most patients with HC and chronic AF have the nonobstructive form of HC, and relatively mild LV hypertrophy.

[A case of Lyme carditis]. / Lyme carditis esete.

The authors introduce their patient suffering from Lyme carditis. This causes III. degree AV block, then spontaneous remission, and complete recovery. Depending on the bases of other scientists' works they introduce their experiences in the clinic and therapy of the disease.

Primary care physicians and children's blood cholesterol.

BACKGROUND. In a national survey sponsored by the National Heart, Lung, and Blood Institute, 62% of primary care physicians of children (under age 18 years) believed that high levels of low-density lipoprotein cholesterol in childhood had a great effect on subsequent heart disease risk. RESULTS. About 75% believed high blood pressure, smoking, and diabetes had similar effects. Although routine cholesterol screening in children under age 10 was infrequent, 72% of physicians screened high risk children. The age at which screening was done varied markedly; more pediatricians screened children younger than 5 years. The majority of physicians who saw children with high blood cholesterol instituted nondrug therapy, with pediatricians being most apt to do so. Low saturated fat diets were prescribed by 26% of these physicians and 9% of physicians prescribed increased polyunsaturated diets. Twelve percent of physicians treating hypercholesterolemic children used lipid-lowering drugs. Among those using drugs, 9% based drug use on total blood cholesterol measurements only. Factors that affected physician treatment of childhood hypercholesterolemia included physician specialty type, organization of practice (group or solo), and the age distribution of the pediatric patient population.

A comparison of sample size methods for the logrank statistic.

Several methods are available for sample size calculation for clinical trials when survival curves are to be compared using the logrank statistic. We discuss advantages and disadvantages of some of these methods, and present simulation results under exponential, proportional hazards and non-proportional hazard situations.

Serial long-term assessment of the natural history of asymptomatic patients with chronic aortic regurgitation and normal left ventricular systolic function.

BACKGROUND: Many asymptomatic patients with aorta regurgitation and normal left ventricular systolic function remain clinically stable for many years, but others ultimately develop symptoms or left ventricular dysfunction and require operation. To identify indexes of left ventricular function predictive of symptomatic and functional deterioration during the long-term course of asymptomatic patients, we studied 104 asymptomatic patients with chronic severe aortic regurgitation and normal left ventricular ejection fraction at rest. METHODS AND RESULTS: Serial echocardiographic (average, 7.8 per patient) and radionuclide angiographic (average, 5.0 per patient) studies were obtained over a mean follow-up period of 8 years (range, 2-16 years). By Kaplan-Meier life table analysis, 58 +/- 9% of patients remained asymptomatic with normal ejection fraction at 11 years, an average attrition rate of less than 5% per year; two patients died suddenly, four developed asymptomatic left ventricular dysfunction, and 19 underwent operation because symptoms developed. By univariate Cox regression analysis, many variables on initial study were associated with death, ventricular dysfunction, or symptoms, including age, left ventricular end-systolic dimension and end-diastolic dimension, fractional shortening, and both rest and exercise ejection fraction (all p less than 0.001). The average rates of change of rest ejection fraction, fractional shortening, and end-systolic dimension were also associated with death or symptoms by univariate Cox analysis (all p less than 0.01). However, when all variables were included in a multivariate Cox analysis, only age (p less than 0.05), initial end-systolic dimension (p less than 0.001), and rate of change in end-systolic dimension and rest ejection fraction during serial studies (both p less than 0.05) predicted outcome. CONCLUSIONS: Thus, in addition to indexes of left ventricular function determined on initial evaluation, serial long-term changes in systolic function identify patients likely to develop symptoms and require operation. Patients have a higher risk of symptomatic deterioration if there is progressive change in end-systolic dimension or resting ejection fraction during the course of serial studies.

Management of cardiovascular disease risk factors in children. A national survey of primary care physicians.

A national survey of family physicians, general practitioners, and pediatricians revealed substantial physician differences in managing cardiovascular disease risk factors in children aged 2 to 18 years. Pediatricians tended to screen younger children but were more conservative in treatment. General practitioners tended to screen less and to initiate intervention in older children, but were more aggressive in therapy. While only 9% of surveyed physicians measured blood cholesterol levels routinely, 72% screened children with family histories of cardiovascular disease. The majority routinely measured blood pressure, but the ages of first measurements differed among physicians. Surprisingly, of those who had treated children with elevated blood pressure or blood cholesterol, 54% said that they had ever used antihypertensive and 12% used lipid-lowering drugs in children, including angiotensin converting enzyme inhibitors and clofibrate. Half the surveyed physicians felt prepared to provide dietary counseling, but only 14% felt successful with it. When asked what they considered were the major cardiovascular risk factors, less than one third of the physicians cited all three major factors: hypertension, hypercholesterolemia, and smoking.

Surrogate endpoints in clinical trials: cardiovascular diseases.

A surrogate endpoint in a cardiovascular clinical trial is defined as endpoint measured in lieu of some other so-called 'true' endpoint. A surrogate is especially useful if it is easily measured and highly correlated with the true endpoint. Often the 'true' endpoint is one with clinical importance to the patient, for example, mortality or a major clinical outcome, while a surrogate is one biologically closer to the process of disease, for example, ejection fraction. Use of the surrogate can often lead to dramatic reductions in sample size and much shorter studies than use of the true endpoint. We discuss several problems common in trials with surrogate endpoints. Most important is the effect of missing data, especially in the face of informative censoring. Possible solutions are the assignment of scores or formal penalties to missing data.